Dual pKa Lipid Nanoparticles for Lung-tropic mRNA Delivery and pH-Programmed Endosomal Escape.

Authors

Seong Gi Lim, Minju Lee, Yiming Wang, Eunjin Choi, Ji Sun Park, Kyungmin Park, Hayoung Jeon, Donghyun Kim, Donghyun Lee, Yeeun Lee, Kee-Pyo Kim, Eunha Kim, Heebeom Koo

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77387. Sep 09, 2026. Epub Sep 09, 2026.

Abstract

Lipid nanoparticles (LNPs) have enabled the clinical application of RNA therapeutics, including approved mRNA vaccines and siRNA medicines. However, their predominant accumulation in liver after systemic administration and inefficient endosomal escape remain key bottlenecks for productive cytosolic delivery and gene expression. Here, we introduce a synthetic ionizable lipid with a dual pKa property that is retained in formulated LNPs. We show that after intravenous injection, these dual pKa LNPs produce lung-selective mRNA expression with higher potency than a cationic lipid-rich comparator while remaining well tolerated. Using molecular dynamics simulations, we find that protonation state can support two distinct interaction modes between the ionizable lipid and endosomal membranes, suggesting a mechanistic basis for efficient endosomal escape. Moreover, the formulation maintains robust pulmonary expression and delivers therapeutic benefit in an acute lung inflammation model. These results establish a structure-property relationship within the ionizable lipid-based LNPs investigated here and identify dual apparent pKa behavior as a promising feature for potent and tolerable lung-targeted RNA delivery.

PMID:
42714328
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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